Carbanilide compositions and methods of using same



United States Patent 3,340,145 CARBANILIDE COMPOSITIONS AND METHODS OFUSING SAME Henry Martin, Basel, Paul Schmidt, Therwil, and Max Wilhelm,Allschwil, Switzerland, assignors to Ciba Corporation, New York, N.Y., acorporation of Delaware N0 Drawing. Filed Jan. 19, 1965, Ser. No.426,679 Claims priority, application Switzerland, Apr. 21, 1961, 4,682/61 Claims. (Cl. 16753) This is a continuation-in-part application of ourapplication Ser. No. 188,520, filed Apr. 18, 1962, now abandoned.

The present invention relates to feedstufis and feedstufr' additivescontaining a carbanilide of the formula X CF; (I)

in which R represents a substituted or unsubstituted aromatic radicaland X stands for O or S, or to the use of such a carbanilide for thepreparation of feedstutfs and feedstuff additives or as an additive tohomegrown animal feeds; also veterinary compositions containing acarbanilide of the above kind, and processes for the preparation of allthese compositions.

It is known that domestic animals, such as ruminants, for example,cattle, sheep or goats, horses, pigs, dogs, cats, furred animals,rabbits, poultry, such as chickens, turkeys, ducks, geese and birds incages, particularly young animals, are exposed to a great number ofenvironmental factors which, in certain cases, can cause an undesirableretardation in growth in spite of a considerably increased food intake.In addition, the average rate of growth or breeding results arediminished by infections or infestations and the losses these entail.

Recently it has been shown that antibiotics, such as tetracyclin,chlorotetracyclin, oxytetracyclin, erythromycin ice cages, ruminants andhorses which are frequently infested by tape-worms, such, for example,as Taenia, Mesocestoide, Diphyllobothrium, Dipylidium in the dog, catand furred animals, and Davainea and Raillietina in birds in cages,Moniezia in ruminants and Anoplocephala in the horse.

The invention also includes veterinary compositions which contain acarbanilide of the defined type together with a carrier. Thesecompositions have a good effect in the intestines of animals, especiallythose mentioned above, against the aforementioned tapeworms, and cantherefore be used with advantage in veterinary medicine.

Carbanilides which are advantageously used in the aforementionedcompositions or are particularly useful for the purposes indicated arethose of the general Formula I in which R stands for a substituted orunsubstituted phenyl radical and X for O or S, the compounds of thegeneral formula 0 a (II) in which R represents an alkyl or alkoxyradical, such as a lower alkyl or lower alkoxy radical, an F, Cl, Br

and procaine-penicillin, and chemotherapeutic agents,

such as sulfaquinoxaline, can bring about a more rapid growth andgreater increase in weight in domestic animals. The mechanismresponsible for this unusual physiological effect consists very probablyin a diminished susceptibility to disease by inhibition of the pathogensand by influencing the bacterial flora in the animals environment or inthe animal itself. In a few cases in which the organisms responsible fordisturbing growth conditions are not influenced by antibiotics with toosmall a therapeutic range,

a specific therapeutic may also produce an analogous effect. Forexample, in cases of coccidiosis growth was considerably promoted inpoultry by administration of small quantities ofdialkyl-dithiocarbamates, dinitro-diphenyl-disulfides, nicarbazin,nitrofurazone and similar I chemotherapeutics. Another means ofinfluencing the growth of domestic animals is in the use of certaintypes of hormoneactive agents, such as stilboestrol. The good resultsare probably due to anabolic activity or protein metabolism by changesin fat metabolism and suppression of normal androgenic function.

It has been found that by using a carbanilide of the above formula whenfeeding domestic animals, such as ruminants, for example, cattle, sheepor goats, horses, pigs, dogs, cats, furred animals, rabbits, poultry,such as chickens, turkeys, ducks, geese and birds in cages, the averagegrowth and an increase in weight or general well-being are promoted andespecially damage caused by vermiculea can be prevented or considerablyweakened. The new feedstuifs or feedstuff additives have a particularlygood effect in furred animals, dogs, cats, birds in or I atom, the groupCF NO CN, SO H, SO NH SO CH --OH, SCN, SO NHA,

v p s SO:N\

' A COOH, --COCH COOA, CONH .-CONHA or CONA A standing for an alkylradical, preferably a lower alkyl radical, n is a whole number from 1 to4, and X represents 0 or S,'deserving special mention.

Particularly valuable is 3:5bis-trifiuoromethyl-4-nitrocarbanilide andthe corresponding thiocarbanilide of the formula I NHONH -No,

wherein X stands for O or S.

As further examples of the compounds of the general Formula I there maybe mentioned: carbanilides of the general formula C F; R1

COOH, COOA, -CONH CONHA or --CONA A standing for a lower alkyl radicaland X for O or S;

, carbanilides of the general formula CFa in which R R and X have themeanings given above; carbanilides of the general formula in which R Rand X have the meanings given above; carbanilides of the general formulaCF: R1 R2 in which R R and X have the meanings given above; carbanilidesof the general formula (ilFg R1 X l C F; R:

in which R R and X have the meanings given above; carbanilides of thegeneral formula X CF,

in which R represents an alkyl or alkoxy radical, an F,- Cl, Br or Iatom, the group CF CN, -SCN, -"SO3H, -SO2NH2, --SO2CH3, -SO2NHA,

/A SO2N A --COOH, -COOA, -CONH CONHA or CONA A standing for a loweralkyl radical and X for O or S;' carbanilides of the general formula amX in which R and X have the meanings given above, for example thecompounds of the formulae I S l The composition of the feedstuflfs orfeedstuff additives to which the above described compounds are addeddepends on the kind of animal to be feed, its age, the ruling marketprice of the feedstuif concerned and other factors. Generally speaking,mixed feedstufis, which contain hydrocarbons, proteins, fats, mineralsand vitamins, are very advantageous. Suitable feed components are, forexample,

corn, milled products, such as flour, groats, shorts of rye,

wheat, barley, oats, buckwheat, maize, sorghum or millet; grass, clover,lucerne flour, molasses, meat scrap, fish, soya and groundnutcake flour,liver oil, lime-powder and bone-meal, thiamine, riboflavin, ascorbicacid or vitamin B or similar feedstuif, mineral or vitamin additives.The new compounds may also be given as a solution or dis persion indrinking water or skimmed milk, if desired in the presence of a suitabledispersant.

The feedstufi s and feedstuff additives of the invention may contain inaddition to the above-mentioned carbanilides other valuable substances,for example antibiotics with a wide therapeutic range, such astetracyclin or chlorotetracyclin, hormones or other compounds having ahormone efliect, such as diethylstilboestr'ol or hexoestrol, or otherfactors stimulating growth, for example alkaloids obtainable from plantsof the Apcoyneae family, such as reserpine, rescinnamine, deserpidine orraunescine or the mother liquors or oleoresins containing thesealkaloids.

In order to obtain the effect desired the carbanilide content of thefeedstulf, which may also be attained by the addition of a feedstufiadditive with a correspondingly higher carbanilide content (e.g. 5 to isadvantageously between about 0.1 to 0.001%, depending onwhether a short(higher doses) or protracted administration is intended. The dailyintake of carbanilide may lie, for example between 20 mg./kg. andmg./kg. body weight.

The veterinary compositions contain advantageously, for example 50 to2000 mg. per dosage unit, depending on the kind of animal. The dailydose is on an average between 30 and 100 mg./kg. bodyweight, thetreatment being carried out for several days, for example on threeconsecutive days. As carriers, the usual excipients may be used, forexample water, gelatin, lactose, starch, magnesium stearate, talc,vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, cholesterolor any other known medicinal excipient. The compositions may be, forexample in the form of tablets, capsules, dragees, powders,suppositories or in liquid form as solutions, for example, assuspensions .or emulsions. They may be sterilized and/or containauxiliaries, such as preserving,- stabilizing, Wetting or emulsifyingagents, taste, odor or color corrigents. They may also contain othermedicinally useful substances. In particular, by the addition of alaxative (for example parafiin oil, castor oil) the excretion of theworms killed or damaged by the effect of the composition may beaccelerated. I

The carbanilides used according to the invention may be prepared by aprocess known per se. The compounds may be obtained, for example, in ageneral way by reacting the starting materials of the general formula IRm for the general Formula H. For example, a compound of the generalformula in which X represents or S is reacted with a compound of thegeneral formula V in which R represents a substituted or unsubstitutedaromatic radical, or a compound of the general formula is reacted with acompound of the general formula RN= :X

in which R and X have the meanings given above.

Thus, in the preparation of the compounds of the invention3:5-trifiuoromethylphenyl isocyanate is reacted, for example, with thefollowing compounds: aniline or substituted anilines for examplepara-chlo raniline,

3 :4-dichloraniline,

3 :S-dichloraniline,

2 -dichloraniline,

3 i4 S-tn'chloraniline,

2 :4 S-trichloraniline, 3-chloro-4-bromaniline,3-chlor-4-methoxy-aniline, 3-chloro-4-methylaniline,3-trifluoromethylaniline, 2-chloro-5-trifiuoromethylaniline,3-trifiuoromethyl-4-chloraniline,

bis-3 :S-trifluorOmethylaniline, 4-bromaniline,

2 4-dichloraniline, 4-aminobenzenesulfonylamide, 4-aminobenzoic acidmethyl ester, 4-butoxyaniline,

4-thiocyananiline,

4-aminoacetophenone, 4-aminophenylacetic acid methyl ester,3-bromaniline, 4-chloro-3-methylaniline, 4-chloro-2-methylaniline,

3 :5dichloro-4-methylaniline,

4-chloro-3 :S-dimethylaniline, hydroxyaminobenzenes, such, for example,as 4- or 5- or 4:5-dichloro-2-amino-l-hydroxybenzene, 3 :4:6-trichloro-2-amino-l-hydroxybenzene, 4- or5-bromo-2-amino-l-hydroxybenzene, 4 6-dibromo-. or

4: 6-dichloro-2-amino-l-hydroxybenzene,

4 S-dibromo-Z-aminol-hydroxybenzene,4-chloro-3-tri-fluoromethyl-2-amino-l-hydroxybenzene.

Or bis-3:5-trifiuoromethylaniline is reacted with a phenylisocyanate ora phenyl-isothiocyanate, for example with one which contains one or morenitro groups, such as 4-nitrophenyl isocyanate, 3-nitroor2-nitro-phenyl-isocyanate, 4-rnethyl-3-nitrophenyl isocy-anate,4-chloro-3- nitrophenylisocyanate, 2-nitro-4-chlorophenyl isocyanate,2-methyl-4-nitro-5-chlorophenyl isocyanate, 2-methoxy-4-nitro-S-chloropheuyl isocyanate or 2:4-dim'tro-phenyl isocayanate.

As feedstuffs or feedstuffs additives the mixtures or premixes shown inthe following examples may be used:

. 6 Example 1 Feedstuff composition (Premix): Grams3:5-bis-trifiuorornethyl-4 nitro-carbanilide or -thiocarbanilide 2.0Wheat standard middlings 7998.0

Total 8000.0

Mixture to be added:

Maize flour 1082.9 Fat 80.0 Fishmeal (60% protein) 100.0 Soybean meal(50% protein) 500.0 Maize gluten 100.0 Lucerne meal 50.0 Corn distillerssolubles 40.0 Calcium carbonate 28.0 Iodized salt 10.0 Vitamin A and ofthe D group (1,000,000 units of A and 250,000 units of D per pound) 4.0Calcium pantothenate 0.25 Butyl-hydroxytoluene 0.25 Choline chloride of25% strength 2.5 Riboflavin (24 grams per pound) 0.1 Vitamin B (0.02gram per pound) 1.0 Methionine 0.5 Manganese sulfate 0.5

Total 2000.0

The mixture to be added is prepared as follows: About half of the maizeflour is put into the mixer, the remainder, to which the heated,liquefied fat has been added, is then added and the whole is mixed untilthe fat is evenly distributed. While mixing, the manganese sulfate,calcium carbonate and iodized salt are then added, followed by the fishmeal, soy bean meal, lucerne meal and maize gluten and the Corndistillers solubles. After mixing thoroughly, the vitamins A and D, thecalcium pantothenate, choline chloride, riboflavin, vitamin B methionineand butyl-hydroxy-toluene are added. The thoroughly mixed premix is thenadded and mixing is continued until all the ingredients are evenlydistributed.

Example 2 Feedstufi additive: Grams 3:S-bis-trifiuoromethyl-4'-nitrocarbanilide or thiocar'banilide Carbo medicinals l5 Cerelose to make1000 The well mixed feedstuffs additive is added to the feed in anamount to give a concentration of about 0.02% of active substance in theuniformly blended mix.

' Grooved tablets are prepared in the conventianal manner with the aboveingredients Weighing 625 mg.

The 3:5 bis trifiuoromethyl 4' nitro-carbanilide used in the aboveexamples may be prepared as follows:

22.9 grams of 3:5-bis-trifluoromethylaniline are dissolved in 100 cc. ofacetonitrile, and the resulting solution treated with a solution of 16.5grams of 4-nitrophenyl isocy-anate in 25 cc. of acetonitrile. Thetemperature rises slowly to 32 C. and is maintained for some hours at 50C., the 3:5 bis-trifluoromethyl 4' nitro-carbanilide slowly spreadingout as a yellow crystalline mass. It melts at 220-225 C., an a secondtime at 300-305 C.

The following compounds are prepared in an analogous manner:

3 :-bis-trifluoromethyl-3'-nitro-oarbanilide, M.P. 230-232 C., 3 :5-bis-trifluoromethyl-3'-nitro-4'-methyl-carbanilide,

M.P. 215-217 C., l V V 3 5-bis-trifluoromethyl-4-bromo-carbanilide, M.P.224-225 .5 C. (recrystallized from acetonitrile), 3:5-bis-triflurornethyl-4'-chloro-carbanilide, M.P.

214.5-215.5 C. (recrystallized from acetonitrile), 3 S-bis-3trifiuoromethyl-lif 5 -dichloro-carbanilide,

M.P. 219-2195 C. (recrystallized from acetonitrile),3:S-bis-trifiuoromethyl-4-fluoro-carbanilide, M.P. 213- 214 C.(recrystallized from acetonitrile), 3 :5 bis-trifluoromethyl-2 :4 5'-trichlorocarbanilide,

M.P. 227-228 C. when recrystallized'from acetoni- "trile, sqlidiliesagain at 229 C. and sublimes at 270- 275 C., V V 3:5-bis-trifloromethyl-4-n-butoxy-carbanilide, M.P. 195-1955? C. (recrystallized fromacetonitrile), 3 z5-bis-trifluoromethyl-3'-chloro-4'-methyl-carbanilide,

M.P. 230-231 C. (recrystallized from acetonitrile), 3 :3S-bis-trifluoromethyl-6'-chloro-carbanilide, M.P.

'225-22 6 C. (recrystallized from acetonitrile), 3 :5-bis-trifluoromethyl-24'-dichloro-carbanilide, M.P.

192-194 C. (recrystallized from acetonitrile), 35-bis-trifluoromethyl-2' :5 '-dichloro-carbanilide, M.P. 225.5227 C.(recrystallized from acetonitrile), 35-bis-trifluoromethyl-3'-chloro-carbanil.ide, M.P.

175-l76 C. (recrystallized from acetonitrile),3:S-bis-trifluoromethyl-3'-bromo-carbanilide melts at 174-175 C. whenrecrystallized from nitromethane and washed with chloroform, 3 :5-bis-trifluoromethyl-3' z4f-dimethyl-ca1'banilide, M.P. 185.5-l86.5 C.(recrystallized from acetonitrile).

The following compounds maybe prepared as follows:

(1) 16.2 grams of 3:4-dichloraniline are dissolved in 150 cc. ofacetonitrile. A solution of 25.5 grams of bis- 3z5-trifluoromethylphenylisocyanate (B.P. 63 C. under 14 mm. of pressure) in 25 cc. ofacetonitrile is added while stirring vigorously. After a short time thecondensation product of the formula l 0 l C F3 01 precipitates. Another25 cc. of acetonitrile are then added,

and the reaction mixture stirred for a few hours. 3:5-bistrifluoromethyl--3':4' dichlorocarbanilide is suctionfiltered, washed with acetonitrileand dried in vacuo. The crude yield is 36 grams, M.P. 223-224 0.; whenrecrystallized from acetonitrile the product melts at 227 C.

(2) 19.5 grams of 4-chloro-3-trifluoromethylaniline are dissolved in 150cc. of acetonitrile; a solution of 25.5 grams ofbis-3:S-trifluoromethyl-phenyl isocyanate in 25 cc. of acetonitrile isadded while stirring vigorously. Condensation is carried out with gentleheating, no precipitation taking place. By evaporation in vacuo there isobtained tri-3z5'z5-trifiuoromethyl 4' chloro diphenyl urea in the formof an oil which soon solidifies. The melting point of the crude productis 178-182 C.; after recrystallization from chlorobenzene at 177178 C.The

condensation may also be carried out in chlorobenzene,

the urea immediately precipitating as crystals.

(3) 22.9 grams of bis-3:5 trifluoromethylaniline are dissolved in 100cc. of acetonitrile; 25.5 grams of bis-3:5- trifluoromethylphenylisocyanate dissolved in 20 cc. of actonitrile are added while stirringthoroughly. The temperature rises to 32 C., but thesolutionremainsclear; Condensation may also be performed without a solvent, by heatingthe components directly on a water bath. The product is ground inbenezene and suction-filtered. When recrystallized from nitromethane3:5:3':5' -tet1'atrifluoromethyl-carbanilide melts at 253256 C. Thecarbanilide is also obtained by boiling3:5-bis-trifluoromethylphenyl-isocyanate with the calculated quantity ofwater in acetonitrile.

(4) 19.32 grams of trifluoromethylaniline are dissolved in cc. ofacetonitrile; 30.5 grams of bis-3:5-trifluoromethylphenyl isocyanatedissolved in 30 cc. of acetonitrile are then added. After 2 hours thesolvent is evaporated in vacuo. The crude product is recrystallized fromchlorobenzene and melts at 167 C.

(5) 17.75 grams of 3-chloro-4-methoxyaniline (orthochloropara-anisidine)are dissolved in 100 cc. of acetonitrile; 3:S-bis-trifluoromethylphenylisocyanate is allowed to run into the solution. The reaction mixturewarms up to 42 C., 3:5-bis-trifluoromethyl-3'-chloro-4'methoxycarbanilide partially precipitating. The condensation prod-- netis recrystallized from acetonitrile and melts at 188- C.

(6) 22.9 grams of 3:5-bis-trifluoromethylaniline are mixed with 18.9grams of finely powdered 2-ch10r0-4-nitrophenyl isocyanate and heated ona water bath, the reaction mixture solidifying with a strong evolutionof heat. The condensation product is pulverized, extracted with benzeneand the residue dried. The crude yield is 40 grams. With the addition ofanimal carbon, 3:5-bis-trifiuoromethyl-2'-chloro-4'-nitro-carbanilidecrystallizes out from acetonitrile in the form of almost colorless, longradiating needles and melts at 211-212 C.

(7) 16.2 grams of 3:4-dichloroaniline are dissolved in a littleacetonitrile and added to 27 grams of 3:5-bis-trifluoromethylphenylisothiocyanate (B.P. 83 C. under 12.

mm. of pressure). The reaction mixture heats up within a short time to82 C.; it is maintained for 1 hour on a boiling water bath and thenevaporated in vacuo. The 3 :5-bistrifiuoro-methyl-3':4-dichloro-thiocarbanilide remains behind as asolid mass whichis recrystallized from benzene. The melting point of thepurified product is 138-139 C. In an analogous manner the followingcompounds are obtained: 3:5-bis-trifluor0methyl-2':3'dichlorocarbanilide,

M.P. 222.5-223.5 C. (recrystallized from acetonitrile);

orated in vacuo and heated for 2 hours at 90 C. Thesolid crude productmelts at 139-141 0.; it is heated in a little benzene (plus animalcarbon) and the filtered warm solution treated with thesame volume ofcyclohexane, 3 3' 5-bis-trifluoromethyl-4 chlorothiocarbanilidecrystallizing out. It melts at 138.5-139 C.

(9) 16.5 grams of para-aminobenzoic acid ethyl ester are dissolved in100 cc. of acetonitrile and stirred with a solution of 25.5 grams of3:5-bis-trifluoromethylphenyl isocyanate in 20 cc. of acetonitrile. Thecondensation product precipitates after a few minutes. It is allowed tostand overnight, then suction-filtered and dried in vacuo at 60 C. Thecrude yield is 39 grams; the melting point lies at 230-231 C.Recrystallized from about 500 cc. of

acetonitrile, 3 S-bis-trifluoromethyl 4' carbethoxy carbanilide melts at230-231 C.

(10) Bis-3:3:S-trifluoromethyl-thiocarbanilide is prepared according tothe method described in (9); the crude product is dissolved with heatingin benzene, treated with animal carbon, filtered and the clear solutiontreated with the same volume of cyclohexane, crystallization setting in;

9 MP. 133-134 C. 3:5-bis-trifluoromethyl-4'-bromo-thiocarbanilide isprepared correspondingly; when recrystallized from benzene-l-cyclohexaneit melts at 163-164 C.

(11) A solution of 25.5 grams of 3:5-bis-tn'fluoromethylphenylisocyanate in 20 cc. of acetonitrile is added to a solution of 17.1grams of para-aminophenyl methyl sulfone in 100 cc. of acetonitrile. Thetemperature is maintained at 65 C. while stirring vigorously,3:5-bis-trifluoromethyl-4-methyl sulfone carbanilide precipitating incrystalline form overnight. It is recrystallized from acetonitrile andmelts then at 224-2255 C.

(12) 27.1 grams of 3:S-bis-trifluoromethylphenyl iso thiocyanate aretreated with 22.9 grams of 3 :S-bis-trifluoromethylaniline without theaddition of any solvent, and heated on a boiling water bath. Thereaction mixture solidifies to form a crystalline cake. 3:3':5:-tetra-trifluoromethyl-thiocarbanilide melts at 184.5-186 C. whenrecrystallized from nitromethane and washed with benzone.

(13) 17.2 grams of sulfanilamide are dissolved in 180 cc. ofacetonitrile with gentle heating; a solution of 25.5 grams of325bis-trifiuoromethylphenyl isocyanate in 25 cc. of acetonitrile isadded while the reaction mixture is stirred vigorously. The reactionmixture heats up slowly to 45 C. and is maintained at a temperature of65 C. for 3 hours, 3:5-bis-trifluoromethyl 4' sulfamidocarbanilideprecipitating. Recrystallized from acetonitrile the product melts at228230 C.

(14) 3:5-bis-trifluoromethyl 4' chlorothiocarbanilide is prepared in ananalogous manner to the product described in (8). When recrystallizedfrom a mixture of benzene and cyclohexane it melts at ISO-151 C.

(15) 17.8 grams of para-dimethylamino-phenyl isothiocyanate and 22.9grams of 3:5-bis-trifluoromethylaniline are heated together on a boilingwater bath for a few hours. The initially liquid reaction mixturebecomes solid after some time to form a crystalline mass.

The latter is suction-filtered and 3:5-bis-trifluoromethyl 4-dimethylamino-thiocarbanilide recrystallized from benzene.

(16) 16.5 grams of para-a-mino-benzoic acid ethyl ester are dissolved in15 cc. of acetonitrile and treated with 27.1 grams of3:5-bis-trifluorornethylphenyl isothiocyanate. The temperature rises to65 C. after a short time; soon afterwards, 3 :S-bis-trifiuoromethyl 4'carbethoxythiocarbanilide precipitates. The product is dried in vacuoand recrystallized from acetonitrile; M.P. 147.5-148 C.

(17) 21.5 grams of thiocyananiline are dissolved in 100 cc. ofacetonitrile and treated, .while being stirred vigorously, with 36.5grams of 3:5-bis-trifluoromethylphenyl isocyanate dissolved in 30 cc. ofacetonitrile. The reaction mixture heats up to 50 C. After beinginoculated, 3:5-bis-trifluoromethyl 4' thiocyan-carbanilide precipitatesin crystalline form; it is recrystallized from acetonitrile and melts at204-205 C.

(18) 13.5 grams of para-amino-acetophenone are dissolved in 100 cc. ofacetonitrile and treated with a solution of 25.5 grams of3:5-bis-trifluoromethylphenyl isocyanate in 25 cc. of acetonitrile withvigorous stirring. After a few seconds3:5-bis-trifluoromethyl-4'-acetocarbanilide precipitates. It issuction-filtered, recrystallized from butanol and washed withacetonitrile. Melting point: 238-239 C.

(19) 11.8 grams of para-aminobenzonitrile are dissolved in 100 cc. ofacetonitrile and treated with a solution of 25.5 grams of3:S-bis-trifluoromethylrjhenyl isocyanate in 25 cc. of acetonitrile.After some time 3:5- bis-trifiuorornethyl-4-cyancarbanilideprecipitates; it is suction-filtered and recrystallized fromacetonitrile. Melting point: 252-253 C.

(20) 27.8 grams of meta-methylthioaniline are dissolved in 100 cc. ofacetonitrile and treated with 51 grams of 3:5-bis-trifluoromethyl-phenylisocyanate in acetonitrile. From the reaction mixture heated to 60 C.3:5-bis-trifluoromethyl3'-thiomethyl-carbanilide precipitates onlyslowly; it is then suction-filtered, washed and recrystallized fromacetonitrile. Melting point 158- 159.5 C.

(21) 3:5 bis-trifiuoromethyl-3' thiomethyl-thiocarbanilide is preparedfrom 3:5-bistrifiuoromethylphenyl isothiocyanate and freshly distilled3-methylthioaniline. When recrystallized from a mixture of benzene andcyclohexane it melts at 125-127 C.

(22) 3 :5 -bis-trifluoromethyl 2':4':6'-trichlo rocarbanilide isobtained by condensing 3:5-bis-trifiuoromethylphenyl isocyanate and2:4:6-trichloraniline in acetonitrile at 60 C. The product melting at225-227 C. becomes solid again at 229 C. and subli-mes at about 295 C.

(23) 21.2 grams of 2-chloro-6-methylaniline are dissolved in 100 cc. ofacetonitrile and 38.25 grams of 3:5- bis-trifluoromethylphenylisocyanate are added dropwise to the solution.3:5-bis-trifluoromethyl-2'-chloro-6'-rnethylcarbanilide precipitatesimmediately. When recrystallized from acetonitrile it melts at 227 C.

(24) 10 grams of 3:5 bis-trifluoromethylaniline are added to a solutionof 10 grams of 2-methylsulfonyl-4- nitroaniline in 100 cc. ofdimethylforrnamide and the whole is heated for 2 hours at C., thencooled and 100 cc. of water added. A precipitate settles out which isfiltered off. For the purpose of purification the product isrecrystallized from a mixture of alcohol and water, to yield 3:5bis-trifiuoromethyl-Z-methylsulfonyl-4-nitroca-rbanilide in the form ofcrystals meltings at 227- 230 C.

(25) 10 grams of 3:5-bis-trifiuoromethylphenyl isocy-.

anate are added to a solution of 10 grams of2-ethylsulfonyl-S-trifluoromethylaniline in 100 cc. of dimethylformamideand the whole is heated for 2 hours at 50 C. On the addition of Water acrystalline precipitate settles out which is recrystallized from amixture of methylene chloride and petroleum ether to yield3:5-bis-trifluoro-' off which crystallizes after being allowed to standfor.

some time. By recrystallization from a mixture of alcohol and waterthere is obtained 3:5-bis-trifluoromethyl-3':5'-

dinitro-4-methoxy-carbanilide in the form of crystals melt ing at226-228 c.

(27) A solution of 5.0 grams of 4-nitro-aniline and 10.0 g. of3,5-bis-trifluoromethyl-phenyl isothiocyanate in 50 cc. of acetonitrileis heated for 4 hours at 80 C. After cooling, 100 cc. of water is addedat room temperature,

whereupon the 3:5-bis-tIifluoromethyl-4'-nitro-thiocarbanilideprecipitates. After recrystallization from dimethylin which R representsphenyl and X stands for a member selected from the group consisting of Oand S, and a feedstuff.

11' 2. A feedstuft' additive composition comprising about 0.195 to about.00ll% of a carbanilide of the formula in which R represents phenyl andX stands for a member selected from the group consisting of O and S, anda feedstufif.

3. A feedstuff composition comprising a carbanilide of the formula I R(n) I X C F;

cooH, cocn -COOA, --CONH CONHA and -CONA A representing lower alkyl, nis a whole number from 1 to 4 and X stands for a member selected fromthe group consisting of O and S, and a feedstuff.

4. A feedstufi additive composition comprising a carbanilide in excessof the therapeutic dosage, said carbanilide being of the formula inwhich R represents a member selected from the group consisting of loweralkyl, lower alkoxy, F, Cl, Br, I, CF -NO CN, -SO H, SO NH SO CH -OH,--SCN, SO N HA,

COOH, -COCH COOA, CONH -CONHA and CONA A representing lower alkyl, n isa whole number from 1 to 4 and X stands for a member selected from thegroup consisting of O and S, and a feedstuff.

12 5. A feedstufi composition comprising acompound of the formula X C Fa wherein X stands for a member selected from the group consisting of Oand S, and a feedstutf.

6. A feedstufi additive composition comprising a compound of the formulabeing in an amount greater than the therapeutically efiective amount.

7. A process for efiecting enhanced growth and wella being whichcomprises administering orally to an animal a composition as claimed inclaim 1.

8. A process for effecting enhanced growth and wellbeing which comprisesadministering orally to an animal a composition as claimed in claim 3.

9. A process for effecting enhanced growth and wellbeing, whichcomprises administering orally to an animal a composition as claimed inclaim 5.

10. A feedstuff composition as claimed in claim 1, wherein the contentof carbanilide compound is between 0.1 and 0.001%.

11. A feedstufi composition as claimed in claim 3, wherein the contentof carbanilide compound is between 0.1 and 0.001%.

12. A feedstulf composition as claimed in claim 5, wherein the contentof carbanilide compound is between 0.1 and 0.001%. 0

13. A process for effecting enhanced growth and wellbeing whichcomprises orally administering to an animal a composition as claimed inclaim 10.

14. A process for effecting enhanced growth and wellbeing whichcomprises orally administering to an animal a composition as claimed inclaim 11.

15. A process for effecting enhanced growth and wellbeing whichcomprises orally administering to an animal a composition as claimed inclaim 12.

References Cited SAM ROSEN, Primary Examiner. JULIUS S LEVITT, AssistantExaminer,

1. A FEEDSTUFF COMPOSITION COMPRISING A CARBANILIDE OF THE FORMULA